Mechanisms of copper homeostasis in bacteria

Abstract

Copper is an important micronutrient required as a redox co-factor in the catalytic centers of enzymes. However, free copper is a potential hazard because of its high chemical reactivity. Consequently, organisms exert a tight control on Cu+ transport (entry-exit) and traffic through different compartments, ensuring the homeostasis required for cuproprotein synthesis and prevention of toxic effects. Recent studies based on biochemical, bioinformatics, and metalloproteomics approaches, reveal a highly regulated system of transcriptional regulators, soluble chaperones, membrane transporters, and target cuproproteins distributed in the various bacterial compartments. As a result, new questions have emerged regarding the diversity and apparent redundancies of these components, their irregular presence in different organisms, functional interactions, and resulting system architectures.

Bacterial copper storage proteins

“…A role for these proteins in Cu(I) storage is currently the most logical suggestion for their function, but in many cases what they are storing Cu for remains unknown. The presence of bacterial Cu storage proteins seems consistent with a number of other observations: (1) that bacterial Cu-import systems exist (6,7,17,21,52,56,77,95), including into the cytosol; (2) that endogenous pools of the metal are available in bacteria (11,15,16,18,96); and (3) that E. coli grown in both LB and minimal medium accumulates Cu (97). It also highlights that there are alternative mechanisms to using different cellular compartments to prevent mis-metallation of proteins by Cu (37).…”

“…A well-characterized family of Cu-homeostasis proteins are the Cu-transporting Ptype ATPases, which can remove this metal ion from the cytosol (4)(5)(6)(7)(20)(21)(22)(23)(24). In eukaryotes, these Cu-efflux pumps work with a cytosolic Cu metallochaperone (the well-characterized ATOX1 in humans and Atx1 in yeast) to facilitate import into the trans-Golgi network for secreted Cu enzymes (4,5,19,24,25).…”

Tracking metal ions through a Cu/Ag efflux pump assigns the functional roles of the periplasmic proteins

“…Activation of CusR results in the production of the periplasmic copper efflux pump CusCFBA, which is specific to cuprous and argentous ions (15) and is essential to copper resistance in E. coli (10,16) under anaerobic conditions. CusCFBA is composed of the inner membrane-bound proton-substrate antiporter CusA, the periplasmic adapter protein (PAP) CusB, and the outer membrane factor (OMF) CusC (17,18). The Cus system is distinguished from other RND-type efflux pumps such as AcrB-TolC and its homologs (19), both by its association with the periplasmic metallochaperone CusF (20,21) and by the active involvement of its periplasmic adapter protein.…”

Mechanism of ATPase-mediated Cu+ Export and Delivery to Periplasmic Chaperones

“…It plays important catalytic roles as a prosthetic group in different enzymes (1)(2)(3). However, it also can be toxic due to its participation in Fenton chemistry and interference in [Fe-S] protein assembly (4,5).…”

“…How are these integrated and connected? P 1B-1 -type Cu ϩ -ATPases use the energy provided by ATP hydrolysis to drive the efflux of cytoplasmic Cu ϩ across cell membranes (15,16) and are required for maintaining cytoplasmic Cu ϩ levels (1,7). Recently, the metallation of membrane and periplasmic cuproproteins has been linked to their pumping of Cu ϩ into the bacterial periplasmic space (14,17,18).…”